Document Detail


Hepoxilin A(3) facilitates neutrophilic breach of lipoxygenase-expressing airway epithelial barriers.
MedLine Citation:
PMID:  23045615     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A feature shared by many inflammatory lung diseases is excessive neutrophilic infiltration. Neutrophil homing to airspaces involve multiple factors produced by several distinct cell types. Hepoxilin A(3) is a neutrophil chemoattractant produced by pathogen-infected epithelial cells that is hypothesized to facilitate neutrophil breach of mucosal barriers. Using a Transwell model of lung epithelial barriers infected with Pseudomonas aeruginosa, we explored the role of hepoxilin A(3) in neutrophil transepithelial migration. Pharmacological inhibitors of the enzymatic pathways necessary to generate hepoxilin A(3), including phospholipase A(2) and 12-lipoxygenase, potently interfere with P. aeruginosa-induced neutrophil transepithelial migration. Both transformed and primary human lung epithelial cells infected with P. aeruginosa generate hepoxilin A(3) precursor arachidonic acid. All four known lipoxygenase enzymes capable of synthesizing hepoxilin A(3) are expressed in lung epithelial cell lines, primary small airway epithelial cells, and human bronchial epithelial cells. Lung epithelial cells produce increased hepoxilin A(3) and lipid-derived neutrophil chemotactic activity in response to P. aeruginosa infection. Lipid-derived chemotactic activity is soluble epoxide hydrolase sensitive, consistent with hepoxilin A(3) serving a chemotactic role. Stable inhibitory structural analogs of hepoxilin A(3) are capable of impeding P. aeruginosa-induced neutrophil transepithelial migration. Finally, intranasal infection of mice with P. aeruginosa promotes enhanced cellular infiltrate into the airspace, as well as increased concentration of the 12-lipoxygenase metabolites hepoxilin A(3) and 12-hydroxyeicosa-5Z,8Z,10E,14Z-tetraenoic acid. Data generated from multiple models in this study provide further evidence that hepoxilin A(3) is produced in response to lung pathogenic bacteria and functions to drive neutrophils across epithelial barriers.
Authors:
David L Tamang; Waheed Pirzai; Gregory P Priebe; David C Traficante; Gerald B Pier; John R Falck; Christophe Morisseau; Bruce D Hammock; Beth A McCormick; Karsten Gronert; Bryan P Hurley
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Publication Detail:
Type:  Clinical Trial; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-10-08
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  189     ISSN:  1550-6606     ISO Abbreviation:  J. Immunol.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-05     Completed Date:  2013-01-15     Revised Date:  2013-12-04    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4960-9     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
8,11,14-Eicosatrienoic Acid / analogs & derivatives*,  immunology,  metabolism
Animals
Arachidonate 12-Lipoxygenase / immunology*,  metabolism
Blood-Air Barrier / immunology*,  metabolism,  microbiology
Epithelial Cells / immunology,  metabolism,  microbiology
Female
Humans
Male
Mice
Neutrophils / immunology*,  metabolism
Pneumonia, Bacterial / immunology,  metabolism
Pseudomonas Infections / immunology*,  metabolism
Pseudomonas aeruginosa / immunology*
Respiratory Mucosa / immunology,  metabolism,  microbiology
Transendothelial and Transepithelial Migration / immunology*
Grant Support
ID/Acronym/Agency:
1 R01 AI095338-01A1/AI/NIAID NIH HHS; 5K22AI065425-02/AI/NIAID NIH HHS; DK 33506/DK/NIDDK NIH HHS; DK 56754/DK/NIDDK NIH HHS; EY016136/EY/NEI NIH HHS; K22 AI065425/AI/NIAID NIH HHS; R01 AI091699/AI/NIAID NIH HHS; R01 AI091699/AI/NIAID NIH HHS; R01 AI095338/AI/NIAID NIH HHS; R01 DK056754/DK/NIDDK NIH HHS; R01 ES002710/ES/NIEHS NIH HHS; R01 GM31278/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
7324-41-6/8,11,14-Eicosatrienoic Acid; 85589-24-8/8-hydroxy-11,12-epoxyeicosa-5,9,14-trienoic acid; EC 1.13.11.31/Arachidonate 12-Lipoxygenase
Comments/Corrections

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